Integrative Molecular Phenotyping
INTEGRATIVE MOLECULAR
PHENOTYPING
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY

PubMed

Endogenous Ketone Bodies Are Associated with Metabolic Vulnerability and Disability in Multiple Sclerosis

Wed, 26/02/2025 - 12:00
Nutrients. 2025 Feb 11;17(4):640. doi: 10.3390/nu17040640.ABSTRACTPurpose: Ketone bodies could be useful biomarkers in multiple sclerosis (MS) because the pathophysiological processes underlying MS disease progression induce metabolic stress. The purpose was to assess the relationships of ketone bodies with biomarkers of metabolic, inflammatory, and oxidative stress in MS. Methods: Blood samples and neurological assessments were obtained from 153 healthy controls (HC), 187 relapsing-remitting (RRMS), and 91 progressive MS (PMS) patients. AcAc, BHB, and acetone were measured using proton nuclear magnetic resonance spectroscopy. Indices of inflammatory vulnerability (IVX), metabolic malnutrition (MMX), and metabolic vulnerability (MVX) were computed from the NMR profiles. Cholesterol, apolipoprotein, lipid peroxidation, and antioxidant profiles were obtained. Regression analysis adjusted for age, sex, body mass index, and HC, RRMS, or PMS disease status. Results: AcAc and BHB levels were greater in MS compared to HC. BHB and ketone bodies were positively associated with disability on the MS Severity Scale and ambulation time. BHB was positively associated with IVX, MMX, and MVX. AcAc was positively associated with MMX and negatively associated with IVX and MVX. Total ketone body concentration was positively associated with MMX and MVX. BHB and AcAc levels were negatively associated with the amino acids alanine, valine, and leucine. Conclusions: Ketone bodies are associated with inflammatory vulnerability, metabolic vulnerability, and ambulatory disability measures in MS.PMID:40004969 | DOI:10.3390/nu17040640

The Impact of the Competition on miRNA, Proteins, and Metabolites in the Blood Exosomes of the <em>Yili</em> Horse

Wed, 26/02/2025 - 12:00
Genes (Basel). 2025 Feb 15;16(2):224. doi: 10.3390/genes16020224.ABSTRACTPURPOSE: Horse racing may cause stress-induced physiological changes and tissue damage in horses, but the changes in miRNA expression, protein expression, and metabolic substances in the plasma exosomes of the Yili horse after racing are still unclear. This study detected miRNA, protein expression, and metabolic substances in the plasma exosomes of Yili horses before and after competition, providing new insights for post-race recovery and care of Yili horses.METHOD: Eight three-year-old Yili horses that had undergone training were selected as the research subjects, with four horses that had not competed as the control group and four horses that had participated in the competition for half an hour as the training group. Extract whole blood and separate plasma from two groups of horses, and then extract plasma exosomes; MiRNAs, proteins, and metabolites in extracellular vesicles were detected and analyzed using miRNAomics, proteomics, and metabolomics. P Result: After the competition, the levels of miRNAs related to the cytoplasm and nucleus in Yili horse plasma exosomes increased, and miRNAs related to the transcription and transcriptional regulation of biological processes significantly increased. The levels of proteins related to the cytoplasm and nucleus also increased, and the levels of proteins related to cell signaling function increased, carbohydrates and their metabolites were significantly reduced.CONCLUSIONS: The competition process causes significant changes in the miRNA, proteomics, and metabolomics of plasma exosomes in the Yili horses, which are mainly related to metabolic regulation.PMID:40004554 | DOI:10.3390/genes16020224

Effects of Combined Transcriptome and Metabolome Analysis Training on Athletic Performance of 2-Year-Old Trot-Type Yili Horses

Wed, 26/02/2025 - 12:00
Genes (Basel). 2025 Feb 4;16(2):197. doi: 10.3390/genes16020197.ABSTRACTOBJECTIVES: Training is essential for enhancing equine athletic performance, but the genetic mechanisms that regulate athletic performance are unknown. Therefore, this paper aims to identify candidate genes and metabolic pathways for the effects of training on equine athletic performance through multi-omics analyses.METHODS: The experiment selected 12 untrained trot-type Yili horses, which underwent a 12-week professional training program. Blood samples were collected at rest before training (BT) and after training (AT). Based on their race performance, whole blood and serum samples from 4 horses were chosen for transcriptomic and metabolomic analyses.RESULTS: The race performance of the horses is dramatically improved in the AT period compared to the BT (p < 0.01) period. The transcriptome analysis identified a total of 57 differentially expressed genes, which were significantly enriched in pathways related to circadian entrainment, steroid hormone biosynthesis, chemokine signaling, and cholinergic synapses (p < 0.05). Additionally, metabolomic analysis revealed 121 differentially identified metabolites, primarily enriched in metabolic pathways such as histidine metabolism, purine metabolism, and the PI3K-Akt signaling pathway. The integration of transcriptomic and metabolomic analyses uncovered five shared pathways, and further combined pathway analyses identified eight differentially expressed genes that correlate with 19 differentially identified metabolites.CONCLUSIONS: The current findings will contribute to establishing a theoretical framework for investigating the molecular mechanisms of genes associated with the impact of training on equine athletic performance. Additionally, these results will serve as a foundation for enhancing the athletic capabilities of trot-type Yili horses.PMID:40004526 | DOI:10.3390/genes16020197

Neuronal polyunsaturated fatty acids are protective in ALS/FTD

Tue, 25/02/2025 - 12:00
Nat Neurosci. 2025 Feb 25. doi: 10.1038/s41593-025-01889-3. Online ahead of print.ABSTRACTHere we report a conserved transcriptomic signature of reduced fatty acid and lipid metabolism gene expression in a Drosophila model of C9orf72 repeat expansion, the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), and in human postmortem ALS spinal cord. We performed lipidomics on C9 ALS/FTD Drosophila, induced pluripotent stem (iPS) cell neurons and postmortem FTD brain tissue. This revealed a common and specific reduction in phospholipid species containing polyunsaturated fatty acids (PUFAs). Feeding C9 ALS/FTD flies PUFAs yielded a modest increase in survival. However, increasing PUFA levels specifically in neurons of C9 ALS/FTD flies, by overexpressing fatty acid desaturase enzymes, led to a substantial extension of lifespan. Neuronal overexpression of fatty acid desaturases also suppressed stressor-induced neuronal death in iPS cell neurons of patients with both C9 and TDP-43 ALS/FTD. These data implicate neuronal fatty acid saturation in the pathogenesis of ALS/FTD and suggest that interventions to increase neuronal PUFA levels may be beneficial.PMID:40000803 | DOI:10.1038/s41593-025-01889-3

S100P is a core gene for diagnosing and predicting the prognosis of sepsis

Tue, 25/02/2025 - 12:00
Sci Rep. 2025 Feb 25;15(1):6718. doi: 10.1038/s41598-025-90858-8.ABSTRACTSepsis, characterized as a severe systemic inflammatory response syndrome, typically originates from an exaggerated immune response to infection that gives rise to organ dysfunction. Serving as one of the predominant causes of death among critically ill patients, it's pressing to acquire an in-depth understanding of its intricate pathological mechanisms to strengthen diagnostic and therapeutic strategies. By integrating genomic, transcriptomic, proteomic, and metabolomic data across multiple biological levels, multi-omics research analysis has emerged as a crucial tool for unveiling the complex interactions within biological systems and unraveling disease mechanisms in recent years. Samples were collected from 23 cases of sepsis patients and 10 healthy volunteers from January 2019 to December 2020. The protein components in the samples were explored by independent data acquisition (DIA) analysis method, while Circular RNA (circRNA) categories were usually identified by RNA sequencing (RNA-seq) technology. Subsequent to the above steps, data quality monitoring was performed by employing software, and unqualified sequences were excluded, and conditions were set for differential expression network analysis (protein group and circRNA group were separately used log2 |FC|≥ 1 and log2 |FC|≥ 2, P < 0.050). Gene Ontology (GO) enrichment analysis and gene set enrichment analysis (GSEA) analysis were performed on common differentially expressed proteins, followed by protein-protein interaction between common differentially expressed genes and cytoscape software enrichment analysis, and subsequently its association with associated diseases (Disease Ontology (DO)) was investigated in an all-round manner. Afterwards, the distribution distinction of common differentially expressed genes in sepsis group and healthy volunteer group was displayed by heat map after Meta-analysis. Subsequent to the above procedures, pivotal targets with noticeable survival curve distinctions in two states were screened out after Meta-analysis. At last, their potential value was verified by in vitro cell experiment, which provided reference for further discussion of the diagnostic value and prognostic effect of target gene. A total of 174 DEPs and 308 DEcircRNAs were identified in the proteomics analysis, while a total of 12 common differentially expressed genes were identified after joint analysis. The protein-protein interaction (PPI) network suggested the degree of interaction between the dissimilar genes, and the heat map demonstrated their specific distribution in distinct groups. Through enrichment analysis, these proteins predominantly participated in a sequence of crucial processes such as intracellular material synthesis and secretion, changes in inflammatory receptors and immune inflammatory response. The meta-analysis identified that S100P is highly expressed in sepsis. As illustrated by the ROC curve, this gene has high clinical diagnostic value, and utimately confirmed its expression in sepsis through in vitro cell experiments. In these two groups of healthy people and septic patients, S100P demonstrated a more obvious trend of differential expression; Cell experiments also proved its value in diagnosis and prognosis judgment in sepsis; As a result, they may become diagnostic and prognostic markers for sepsis in clinical practice.PMID:40000745 | DOI:10.1038/s41598-025-90858-8

Serum metabolic characteristics associated with the deterioration of colorectal adenomas

Tue, 25/02/2025 - 12:00
Sci Rep. 2025 Feb 26;15(1):6845. doi: 10.1038/s41598-025-91444-8.ABSTRACTColorectal cancer (CRC) can evolve from colorectal adenomas, which can be further classified into non-advanced adenomas (NAAs) and advanced adenomas (AAs) based on their clinical characteristics. Their prognoses are vastly different, with patients with NAAs having significantly lower recurrence and CRC-related mortality rates than those with AA or CRC. Although serum metabolomics has shown promise for the early diagnosis of CRC, the differences in serum metabolite composition between NAA and AA still need to be further elucidated. This study aimed to explore the mechanism of CRC occurrence and development based on the unique serum metabolic fingerprints of different stages of CRC and to discover a new non-invasive diagnostic method based on serum metabolomics. A clinical CRC progression cohort containing healthy control (NC; n = 40), NAA (n = 40), AA (n = 40), and CRC (n = 22) groups was constructed, and untargeted metabolomic analysis based on liquid chromatography/mass spectrometry was performed to analyze the serum metabolite characteristics of each group. A semi-quantitative analysis of intergroup metabolite differences was conducted, focusing on specific metabolites that differed in the NAA and AA groups. Finally, variable metabolites were selected based on least absolute shrinkage and selection operator (LASSO) regression analysis, and receiver operating characteristic curves were plotted to evaluate the efficacy of the serum metabolite-based diagnostic model in distinguishing NC/NAA populations from AA/CRC populations. Metabolomic analysis revealed significant differences in the composition of metabolites in the NC and NAA groups compared to the CRC group, whereas the serum metabolites of the AA group were similar to those of the CRC group. The levels of 33 metabolites were significantly different in the serum of AA/CRC patients compared to that of NAA patients, and their functions included glycerophospholipid, sphingolipid, and caffeine metabolism. LASSO regression analysis identified 57 differential metabolite variables between the NC/NAA and AA/CRC groups. The diagnostic model constructed using the random forest algorithm had the best discrimination effect, with areas under the curve of 1.000 (95% confidence interval [CI] 1.000-1.000) and 0.685 (95% CI 0.540-0.830) for the training and testing sets, respectively. The composition of serum metabolites is specific to the different stages of CRC development. The serum metabolite composition of patients with AAs was similar to that of patients with CRC. Auxiliary diagnostic measures based on serum metabolites have the potential to guide the follow-up and treatment of patients with adenoma.PMID:40000732 | DOI:10.1038/s41598-025-91444-8

TAX1BP1-dependent autophagic degradation of STING1 impairs anti-tumor immunity

Tue, 25/02/2025 - 12:00
Autophagy. 2025 Feb 25. doi: 10.1080/15548627.2025.2471736. Online ahead of print.ABSTRACTThe activation of STING1 can lead to the production and secretion of cytokines, initiating antitumor immunity. Here, we screened an ion channel ligand library and identified tetrandrine, a bis-benzylisoquinoline alkaloid, as an immunological adjuvant that enhances antitumor immunity by preventing the autophagic degradation of the STING1 protein. This tetrandrine effect is independent of its known function as a calcium or potassium channel blocker. Instead, tetrandrine inhibits lysosomal function, impairing cathepsin maturation, and autophagic degradation. Proteomic analysis of lysosomes identified TAX1BP1 as a novel autophagic receptor for the proteolysis of STING1. TAX1BP1 recognizes STING1 through the physical interaction of its coiled-coil domain with the cyclic dinucleotide binding domain of STING1. Systematic mutation of lysine (K) residues revealed that K63-ubiquitination of STING1 at the K224 site ignites TAX1BP1-dependent STING1 degradation. Combined treatment with tetrandrine and STING1 agonists promotes antitumor immunity by converting "cold" pancreatic cancers into "hot" tumors. This process is associated with enhanced cytokine release and increased infiltration of cytotoxic T-cells into the tumor microenvironment. The antitumor immunity mediated by tetrandrine and STING1 agonists is limited by neutralizing antibodies to the type I interferon receptor or CD8+ T cells. Thus, these findings establish a potential immunotherapeutic strategy against pancreatic cancer by preventing the autophagic degradation of STING1.PMID:40000606 | DOI:10.1080/15548627.2025.2471736

Serum Metabolomics Profiling Coupled with Machine Learning Identifies Potential Diagnostic and Prognostic Candidate Markers in Meningioma Using Raman Spectroscopy, ATR-FTIR, and LC-MS/MS

Tue, 25/02/2025 - 12:00
J Proteome Res. 2025 Feb 25. doi: 10.1021/acs.jproteome.4c00806. Online ahead of print.ABSTRACTMeningioma, the most prevalent brain tumor, poses significant challenges due to its unclear transition from low-grade to aggressive forms, with limited knowledge about grade-specific markers. We have utilized vibrational spectroscopic techniques such as ATR-FTIR and Raman spectroscopy, alongside LC-MS/MS-based mass spectrometry to understand the systemic cues and evaluate them for clinical practice. The acquired Raman and ATR-FTIR spectra of 46 meningioma patients (27 low-grade and 19 high-grade) and 8 healthy individuals revealed 98.15% and 83.33% accuracy based on PC-LDA. The grade classification revealed an accuracy of around 70%, implying the presence of subtypes and transition phases. The observed alterations corresponded to lipids, nucleic acids, and proteins. Further, the LC-MS/MS-based study identified different derivatives of cholines, indoles, lipids, sphingosine, tryptophan, and their respective metabolic pathways as contributors in tumorigenesis and progression. Further, PRM-based targeted validation and feature selection was carried out on 43 meningioma patients and 17 healthy controls. Glycochenodeoxycholic acid, indole-3-acetic acid, trans-3-indoleacrylic acid, glycodeoxycholic acid, 5α-dihydrotestosteroneglucornide, and glycocholic acid segregated meningioma samples with an accuracy of around 90% while features like indole-3-acetic acid, stercobilin, sphingosine-1-phosphate, deoxycholic acid, and citric acid could classify grades with around 70% accuracy. These findings suggest that further validation across larger cohorts could enhance its usage in clinical settings.PMID:40000599 | DOI:10.1021/acs.jproteome.4c00806

OsJAZ10 Modulates Metabolite Profiles in Rice Seedlings in Response to Alkaline Stress

Tue, 25/02/2025 - 12:00
Rice (N Y). 2025 Feb 25;18(1):9. doi: 10.1186/s12284-025-00762-y.ABSTRACTThe jasmonate ZIM-domain (JAZ) proteins, known as inhibitors in the jasmonic acid (JA) pathway, have been reported to play a protective role against abiotic stress in plants. Nevertheless, the specific role of JAZ proteins in rice seedlings under alkaline stress remains unexplored. In this study, we mainly focus on OsJAZ10, investigating the physiological response mechanism and metabolic regulation on rice seedlings challenged by alkaline stress. Our results revealed that the antioxidant enzyme activity and osmotic adjustment ability of the OsJAZ10 overexpression lines were less affected by alkaline stress compared to WT (Wild-type) line. Metabolomic analysis demonstrated a significant accumulation of organic acids, including citrate and DL-malate, as well as amino acids such as DL-serine, DL-glutamine, threonine, glycine, and L-glutamate, in the OsJAZ10 overexpression plants in response to alkaline stress. Besides, OsJAZ10 was also involved in pantothenate and CoA biosynthesis, carbon fixation, and C5-branched dibasic acid metabolism in response to alkaline stress. Finally, OsJAZ10 was found to negatively regulated the biosynthesis and signaling of jasmonic acid pathway by repressing JA-responsive genes. Overall, this research elucidates the role of OsJAZ10 in conferring enhanced tolerance to alkaline stress in rice, providing valuable insights for the development of stress-tolerant rice varieties.PMID:40000553 | DOI:10.1186/s12284-025-00762-y

Beyond the surface: the plant secretome as a bridge between the cell and its environment

Tue, 25/02/2025 - 12:00
Planta. 2025 Feb 26;261(4):67. doi: 10.1007/s00425-025-04648-7.ABSTRACTWe describe the biological importance of proteins secreted in plants under different conditions and biological processes, the secretion mechanisms, methodologies for obtaining and identifying these proteins, and future perspectives. Molecule secretion inside and outside the cell is relevant to all areas of plant biology. Protein secretion, in particular, has intriguing possibilities due to the different secretion pathways that the cell uses to send biochemical messages. The secretion of proteins-secretomes-into extracellular space in response to different stimuli or stress situations, in vitro or in planta conditions, has been studied in plants and plant tissues. Proteomics has allowed the quantitative and qualitative analysis of this process and the measurement of proteins associated with the cellular development of different tissues. This has provided the means of evaluating a more precise biochemical state of the cells and the changes that occur during their growth. With the development of new techniques in proteomics, such as mass spectrometry, sequencing, and bioinformatics, it is now possible to elucidate the main proteins secreted, with all their posttranslational modifications, in different plant species and under different specific conditions. This review presents the different pathways of protein secretion in plants, highlighting the well-known importance of signal peptides. The advances and disadvantages of in planta and in vitro systems used for proteomic purposes are discussed. The principal proteomic techniques to better understand the biological function of the secretome are summarized.PMID:40000454 | DOI:10.1007/s00425-025-04648-7

Toward an integrated omics approach for plant biosynthetic pathway discovery in the age of AI

Tue, 25/02/2025 - 12:00
Trends Biochem Sci. 2025 Feb 24:S0968-0004(25)00025-8. doi: 10.1016/j.tibs.2025.01.010. Online ahead of print.ABSTRACTElucidating plant biosynthetic pathways is key to advancing a sustainable bioeconomy by enabling access to complex natural products through synthetic biology. Despite progress from genomic, transcriptomic, and metabolomic approaches, much multiomics data remain underutilized. This review highlights state-of-the-art multiomics strategies for discovering plant biosynthetic pathways, addressing challenges in data acquisition and interpretation with emerging computational tools. We propose an integrated workflow combining molecular networking, reaction pair analysis, and gene expression patterns to enhance data utilization. Additionally, artificial intelligence (AI)-driven approaches promise to revolutionize pathway discovery by streamlining data analysis and validation. Integrating multiomics data, chemical insights, and advanced algorithms can accelerate understanding of plant metabolism and bioengineering valuable natural products efficiently.PMID:40000312 | DOI:10.1016/j.tibs.2025.01.010

Corrigendum to 'A pH-responsive phase-transition bi-affinity nanopolymer-assisted exosome metabolomics for early screening of osteoarthritis' [Talanta 283 (2025) 127144]

Tue, 25/02/2025 - 12:00
Talanta. 2025 Feb 24:127763. doi: 10.1016/j.talanta.2025.127763. Online ahead of print.NO ABSTRACTPMID:40000282 | DOI:10.1016/j.talanta.2025.127763

Exploring Single-Probe Single-Cell Mass Spectrometry: Current Trends and Future Directions

Tue, 25/02/2025 - 12:00
Anal Chem. 2025 Feb 25. doi: 10.1021/acs.analchem.4c06824. Online ahead of print.ABSTRACTThe Single-probe single-cell mass spectrometry (SCMS) is an innovative analytical technique designed for metabolomic profiling, offering a miniaturized, multifunctional device capable of direct coupling to mass spectrometers. It is an ambient technique leveraging microscale sampling and nanoelectrospray ionization (nanoESI), enabling the analysis of cells in their native environments without the need for extensive sample preparation. Due to its miniaturized design and versatility, this device allows for applications in diverse research areas, including single-cell metabolomics, quantification of target molecules in single cell, MS imaging (MSI) of tissue sections, and investigation of extracellular molecules in live single spheroids. This review explores recent advancements in Single-probe-based techniques and their applications, emphasizing their potential utility in advancing MS methodologies in microscale bioanalysis.PMID:39999987 | DOI:10.1021/acs.analchem.4c06824

Common immunotoxicity mechanisms of hepatotoxicity induced by raw Polygonum multiflorum and Polygonum multiflorum praeparata: inhibition of M2 macrophage polarization

Tue, 25/02/2025 - 12:00
Toxicon. 2025 Feb 23:108293. doi: 10.1016/j.toxicon.2025.108293. Online ahead of print.ABSTRACTMacrophage polarization has been linked to hepatotoxicity induced by raw Polygonum multiflorum (RPM) and Polygonum multiflorum praeparata (PMP), but the regulatory mechanisms behind this remain unclear. This study aims to investigate the regulatory effects of RPM and PMP on M2 macrophages and the potential mechanisms. Sprague-Dawley rats were exposed to RPM and PMP under lipopolysaccharide (LPS) stimulation. RAW264.7 cells induced with IL-4 were treated with RPM and PMP. Under LPS stimulation, both RPM and PMP increased serum enzyme levels and pro-inflammatory factor levels and induced histopathological injury. M1 macrophage infiltration and M1 gene expression in the liver increased, whereas M2 macrophage infiltration and M2 gene expression decreased. RPM and PMP inhibited M2 gene expression and reduced green fluorescence intensity. RNA sequencing and metabolomics revealed that RPM regulated sphingolipid signaling and Janus kinase/signal transducer and activator of transcription signaling pathways, while PMP influenced arginine and proline metabolism, arginine biosynthesis, and cholesterol metabolism pathways. RPM and PMP orchestrate distinct signaling pathways, thereby inhibiting M2 macrophage polarization and inducing hepatotoxicity. This study not only elucidates the pathophysiology underlying RPM- and PMP-induced hepatotoxicity, but also provides insights for the development of new therapeutic interventions.PMID:39999927 | DOI:10.1016/j.toxicon.2025.108293

Systematic analysis of relationships between serum lipids with all-cause and cause-specific mortality: Evidence from prospective cohort studies of UK Biobank and Women's Health Initiative

Tue, 25/02/2025 - 12:00
Clin Nutr. 2025 Feb 11;47:94-102. doi: 10.1016/j.clnu.2025.02.009. Online ahead of print.ABSTRACTBACKGROUND & AIMS: Serum lipids, including lipoproteins, cholesterol, and triglycerides, are important modifiable factors influencing human health. However, the associations among different serum lipid profiles and mortality remain insufficiently understood, particularly regarding potential causality and population heterogeneity. This prospective study aims to systematically investigate the relationships between serum lipid concentrations of different densities and sizes with all-cause and cause-specific mortality.METHODS: Cox proportional and Fine-Gray subdistribution hazard models were applied to investigate the associations of 54 lipid concentrations with all-cause and cause-specific mortality (including cardiovascular disease (CVD), cancer, and respiratory disease) in the UK Biobank cohort of 441,448 individuals with 17-year follow-up. Cohorts of 120,967 and 44,168 individuals from the Women's Health Initiative (WHI) with 16-year follow-up and a large-scale meta-analysis were utilized for external replication. We further assessed the underlying causality using Mendelian randomization (MR) and possible modifiers using multiple subgroup analyses.RESULTS: During a median follow-up of 13.8 years, 39,290 deaths occurred, including 7399 from CVD, 18,928 from cancer, and 2707 from respiratory disease. We identified 160 significant associations between lipid concentrations and all-cause and cause-specific mortality. Importantly, most were inverse, with decreased lipid levels linked to increased risk of premature death [hazard ratios (HRs): 0.70-0.98 per standard deviation (SD)]. In contrast, positives were observed for HDL (large/very large) and triglyceride concentrations [HRs: 1.02-1.25 per SD], indicating increased mortality risk with higher levels. Most lipoproteins and cholesterol exhibited nonlinearly correlations with mortality, especially the significant U-shaped in total/HDL. However, MR showed that elevations in several lipids were associated with increased all-cause and CVD-specific mortality risk. Multiple subgroup analyses revealed that age, sex, and lipid-modifying drugs modified the lipid-mortality relationship; specifically, higher lipid concentrations increased mortality risk in younger adults not taking lipid-modifying drugs, but decreased mortality in older adults taking lipid-modifying drugs. The majority of associations were replicated in the WHI and external cohorts.CONCLUSION: Our study systematically reported a large number of associations between serum lipid concentrations and mortality. Subgroup-based population heterogeneity analysis suggests that age, sex, and lipid-modifying drugs could be modifiers for the lipid-mortality relationship. These findings provide more guidance for lipid management and individualized prevention.PMID:39999642 | DOI:10.1016/j.clnu.2025.02.009

MInfer: Bridging MetaboAnalyst and Jacobian analysis for metabolomic networks

Tue, 25/02/2025 - 12:00
Comput Methods Programs Biomed. 2025 Feb 18;263:108672. doi: 10.1016/j.cmpb.2025.108672. Online ahead of print.ABSTRACTBACKGROUND AND OBJECTIVE: Metabolomic interaction networks provide critical insights into the dynamic relationships between metabolites and their regulatory mechanisms. This study introduces MInfer, a novel computational framework that integrates outputs from MetaboAnalyst, a widely used metabolomic analysis tool, with Jacobian analysis to enhance the derivation and interpretation of these networks.METHODS: MInfer combines the comprehensive data processing capabilities of MetaboAnalyst with the mathematical modeling power of Jacobian analysis. This framework was applied to various metabolomic datasets, employing advanced statistical tests to construct interaction networks and identify key metabolic pathways.RESULTS: The application of MInfer revealed significant metabolic pathways and potential regulatory mechanisms across multiple datasets. The framework demonstrated high precision, sensitivity, and specificity in identifying interactions, enabling robust network interpretations.CONCLUSIONS: MInfer enhances the interpretation of metabolomic data by providing detailed interaction networks and uncovering key regulatory insights. This tool holds significant potential for advancing the study of complex biological systems.PMID:39999596 | DOI:10.1016/j.cmpb.2025.108672

Effect and mechanism of calcium ions on the astringency in green tea infusion and epigallocatechin gallate solution: An in vitro oral soft tribology study

Tue, 25/02/2025 - 12:00
Food Chem. 2025 Feb 17;477:143442. doi: 10.1016/j.foodchem.2025.143442. Online ahead of print.ABSTRACTIn this study, the effect of calcium ions (Ca2+) on the astringency sensation in green tea infusion was explored using sensory evaluation, in vitro oral soft tribology, and targeted metabolomics. Ca2+ enhanced the astringency intensity (from 2 to 6) and the turbidity (from 10.0 to 83.3), and decreased the particle size (from 1468.0 to 817.65) in cold-brewing tea. Catechins influenced the astringent sensation in the presence of Ca2+ and the content of (-)-Epicatechin, (-)-Epigallocatechin, and (-)-Epigallocatechin gallate (EGCG) solution in green tea infusion after oral processing all reduced. The friction coefficient of hot-brewed tea (μ, 1.6-2.8) was greater than that of cold-brewed tea (μ, 1.0-2.6), and EGCG increased with the enlarged Ca2+ concentrations. Ca2+ increased the astringency mainly through catechins and saliva lubrication. The in vitro soft oral tribology could be usefully explored the enlarged astringency sensation by Ca2+, and applied to the astringency regulation of beverages.PMID:39999546 | DOI:10.1016/j.foodchem.2025.143442

Salivary metabolites profiling for diagnosis of COPD:an exploratory study

Tue, 25/02/2025 - 12:00
J Breath Res. 2025 Feb 25. doi: 10.1088/1752-7163/adba07. Online ahead of print.ABSTRACTPulmonary function tests (PFTs) are the gold standard for diagnosing of Chronic obstructive pulmonary disease (COPD). Given its limitation in some scenarios, it is imperative to develop new high-throughput screening methods for biomarkers in diagnosing COPD. This study aims to explore the feasibility of screening novel diagnostic biomarkers based on salivary metabolomics for the limited availability of PFTs and difficulties in implementation at primary care facilities.&#xD;&#xD;Methods: Participants were recruited from the outpatient department of West China Hospital. Saliva samples were collected to analyze the metabolites through the UPLC-Q-Exactive Orbitrap-MS platform. The raw data from the mass spectrometer was preprocessed with R software after peak extraction. The Wilcoxon rank sum test, Fold change analysis, PCA and OPLS-DA were used to identify potential biomarkers. The ROC curve was used to assess the diagnostic efficacy of the predictive model generated by potential biomarkers.&#xD;&#xD;Results: Saliva samples were collected from 66 patients with COPD and 55 healthy volunteers. Significant differences in the salivary metabolome between COPD patients and healthy controls were identified, with 261 differential metabolites recognized, 16 of which were considered as potential biomarker. The diagnostic model generated by these 16 biomarkers can successfully distinguish COPD patients from healthy people. &#xD;&#xD;Conclusions &#xD;Salivary metabolomic profiling is likely to emerge as a promising method for screening potential diagnostic biomarkers of COPD. Further prospective studies with large sample size are needed to verify the predictive value of these biomarkers in COPD diagnosis.&#xD.PMID:39999480 | DOI:10.1088/1752-7163/adba07

Ultrasensitive Determination of Amino Acids in Single Cells by Chemical Isotope Labeling with Liquid Chromatography Mass Spectrometry Analysis

Tue, 25/02/2025 - 12:00
Anal Chem. 2025 Feb 25. doi: 10.1021/acs.analchem.4c06441. Online ahead of print.ABSTRACTAmino acids play multiple critical roles in the regulation of various metabolic pathways and physiological processes in living organisms. Mass spectrometry (MS) has become the most pioneering platform for amino acid analysis. However, the simultaneous and sensitive determination of amino acids is still challenging because of their structural similarity and broad ranges of concentrations. To this end, a pair of isotope labeling reagents, d0/d3-2-((diazomethyl)phenyl)(9-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl) methanone (DMPI/d3-DMPI), were applied to label amino acid metabolites. The diazo groups on the pair of isotopomers (DMPI/d3-DMPI) can specifically react with the carboxyl groups on the amino acids. The results showed that the retention on reversed-phase column were enhanced and the detection sensitivities of 19 amino acids were increased benefiting from DMPI labeling strategy that transfers the hydrophobic indole heterocycle group of DMPI to the hydrophilic compounds of amino acids. The obtained limits of detection (LODs) of amino acids were in the range of 0.002-0.082 fmol. With this established method, we achieved the sensitive detection of amino acids in a single HUVE cell. Meanwhile, we found that the contents of amino acids in the serum of premature neonates were higher compared to normal neonates. Overall, this developed method provides great support of detection tool for the clinical metabolomic study of amino acids and the investigation of dynamic changes of amino acid metabolism in single cells.PMID:39999418 | DOI:10.1021/acs.analchem.4c06441

Microbiota contribute to regulation of the gut-testis axis in seasonal spermatogenesis

Tue, 25/02/2025 - 12:00
ISME J. 2025 Feb 25:wraf036. doi: 10.1093/ismejo/wraf036. Online ahead of print.ABSTRACTSeasonal breeding is an important adaptive strategy for animals. Recent studies have highlighted the potential role of the gut microbiota in reproductive health. However, the relationship between the gut microbiota and reproduction in seasonal breeders remains unclear. In this study, we selected a unique single food source animal, the flying squirrel (Trogopterus xanthipes), as a model organism for studying seasonal breeding. By integrating transcriptomic, metabolomic, and microbiome data, we comprehensively investigated the regulation of the gut-metabolism-testis axis in seasonal breeding. Here, we demonstrated a significant spermatogenic phenotype and highly active spermatogenic transcriptional characteristics in the testes of flying squirrels during the breeding season, which were associated with increased polyamine metabolism, primarily involving spermine and γ-amino butyric acid. Moreover, an enrichment of Ruminococcus was observed in the large intestine during the BS and may contribute to enhanced methionine biosynthesis in the gut. Similar changes in Ruminococcus abundance were also observed in several other seasonal breeders. These findings innovatively revealed that reshaping the gut microbiota regulates spermatogenesis in seasonal breeders through polyamine metabolism, highlighting the great potential of the gut-testis axis in livestock animal breeding and human health management.PMID:39999373 | DOI:10.1093/ismejo/wraf036

Pages